Abstract
Compelling evidence has verified that long non-coding RNAs (lncRNAs) play a critical role on drug resistance in various diseases, especially cancer. However, the role of lncRNAs underlying multidrug resistance in epilepsy remains to be clarified. In the present study, we investigated the potential regulatory mechanism of the lncRNA KCNQ1OT1 in regulating antiepileptic drug (AED) resistance in human brain microvascular endothelial cells (HBMECs). The results revealed that expression of P-glycoprotein (P-gp) and KCNQ1OT1 was significantly elevated in phenytoin-resistant HBMECs (HBMEC/PHT). Meanwhile, the activity of nuclear factor-kappa B (NF-κB) was increased in HBMECs/PHT cells. Microarray analysis indicated that miR-138-5p was downregulated in HBMEC/PHT cells. Interestingly, bioinformatics prediction tools indicated miR-138-5p could directly target the transcripts of KCNQ1OT1 and NF-κB p65, and these results were confirmed by luciferase assays. Moreover, KCNQ1OT1 downregulation or miR-138-5p upregulation in vitro could inhibit P-gp expression and suppress NF-κB signaling pathway activation. Additionally, knockdown of KCNQ1OT1 or overexpression of miR-138-5p could increase the accumulation of rhodamine 123 (Rh123) and AEDs in HBMEC/PHT cells. Collectively, our results suggested that KCNQ1OT1 contributes to AED resistance through the miR-138-5p/NF-κB/ABCB1 axis in HBMEC/PHT cells, and these results provide a promising therapeutic target for the treatment of medically intractable epilepsy.
Highlights
Epilepsy is one of the most common neurological disorders, and the main approach to manage epilepsy is still medication therapy
Considering the experience in cancer therapy, we aimed to investigate whether KCNQ1OT1 contributes to antiepileptic drug (AED) resistance via the competing endogenous RNAs (ceRNAs) regulatory mechanism in PHT-resistant human brain microvascular endothelial cells in the present study
The Expression of KCNQ1OT1 Is Upregulated in PHT-Resistant human brain microvascular endothelial cells (HBMECs)
Summary
Epilepsy is one of the most common neurological disorders, and the main approach to manage epilepsy is still medication therapy. Approximately one-third of epilepsy cases are resistant to treatment with antiepileptic drugs (AEDs) and develop into medically intractable epilepsy, which has become a major clinical problem in epilepsy therapy (Kwan et al, 2010). The mechanism underlying drug resistance in epilepsy is multifactorial, involving both genetic and environmental factors (Tang et al, 2017). In the past few decades, overexpression of multidrug efflux transporters at the blood–brain barrier (BBB) has been proposed as one of the most significant factors for drug resistance in epilepsy (Potschka, 2010b). P-glycoprotein (P-gp/ABCB1) is the most investigated member among the multidrug efflux transporters for inducing drug resistance in various cancers (Binkhathlan and Lavasanifar, 2013).
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